Novel Hamster Models of Chikungunya Viral Arthritis - PROJECT SUMMARY Chikungunya virus (CHIKV), a mosquito-borne RNA virus, causes chikungunya fever (CHIKF), typically accompanied by severe, debilitating and often chronic arthralgia. The virus was first associated with human disease in the 1950s in Tanzania, and has re-emerged, causing epidemics in Africa, Asia, Europe, and Americas over the last decade. Neither antiviral treatment nor vaccines are available for CHIKV infection. Animal models have been used to understand CHIKV infection and virus-induced acute and persistent arthralgia. CHIKV infection induces viremia, acute and chronic arthralgia in immunocompetent mice and severe lethal diseases in mice deficient of interferon (IFN)-I signaling. The limitation of murine models of CHIKV infection is that they do not recapitulate human CHIKV diseases completely, in particular CHIKV-induced chronic arthralgia and maternal/neonatal transmission. Thus, development of other feasible small animal models to recapitulate CHIKV-induced human diseases is in high need. The golden Syrian hamster has been used in studying many human viral infections. CHIKV infection in wild-type hamsters induced viremia, rapid virus dissemination to major organs, and histopathologic lesions in limbs and joints as reported in human patients. Nevertheless, infectious virus was cleared within 4 days. Investigation of viral RNA persistence and chronic tissue injury in wild-type and optimized mutant hamsters will be critical for further development of a hamster model of CHIKV infection. Type I and III IFNs contribute to the control of CHIKV infection in mice and cell culture models. Both signaling pathways result in activation of signal transducer and activator of transcription 2 (STAT2). By utilizing the CRISPR/Cas9 system to conduct gene targeting in hamsters, we previously produced STAT2 knockout (KO) hamsters. STAT2 KO hamsters have been used in several other viral disease models to increase viral replication and severity of viral diseases and to recapitulate Zika virus vertical transmission in humans. SARS-CoV-2 replication was also enhanced in hamsters defective of IL28Rα, a subunit of type III IFN receptor compared to wild-type hamsters. Furthermore, adaptive immunity has been shown to play critical roles in controlling CHIKV infection in mice and humans. To further define the hamster as a model for CHIKV infection, we hypothesize that type I and/or III IFNs contribute to control of CHIKV infection, virus-induced tissue inflammation and vertical transmission, and protect host from CHIKV- induced chronic disease via modulating adaptive immune responses in hamsters. We will first determine viral infection, tissue inflammation, and vertical transmission following CHIKV infection in STAT2 KO and IL28Rα KO hamsters. We will also identify the role of humoral and T cell- mediated immune responses in CHIKV-induced chronic diseases in hamsters. Results from this study will not only refine a novel hamster model of CHIKV-induced chronic arthralgia, but also increase our understanding of the pathogenesis of CHIKV infection and vertical transmission.
